Deciphering and exploiting ferroptosis regulatory mechanism in cancer

Introduction

Ferroptosis is a cell death modality triggered by the accumulation of oxidised lipids, a process known as lipid oxidation, and is associated with a multitude of pathological conditions, including ageing, neurodegeneration, and cancer. On the flip side, recent studies demonstrated that targeting pathways contributing to the prevention or repair of oxidised lipids is a powerful strategy to eradicate therapeutically challenging entities, including neuroblastoma, a pediatric malignancy reported to be remarkably sensitive to ferroptosis.

Knowledge Gap

However, therapeutic breakthroughs targeting this pathway are elusive due to our incomplete understanding of the factors controlling this process. DeciFERR will address this critical knowledge gap and identify strategies to trigger ferroptosis. This will be accomplished by discovering and characterising novel mechanisms regulating the stability of key ferroptosis suppressors, thus providing opportunities to develop tailored strategies to target ferroptosis-sensitive entities.

Project Background

This project rests on our pioneering works identifying two major break systems operating against lipid peroxidation:

1. Glutathione peroxidase 4 (GPX4)
2. Ferroptosis suppressor protein 1 (FSP1)

Aim 1

In Aim 1, using a combination of novel cellular models and target-oriented phenotypic screens, we will characterise and target pathways involved in selenocysteine uptake, mobilisation, and recycling, which we found essential for the stability of selenoproteins, including GPX4.

Aim 2

In Aim 2, we will dissect metabolic and cellular states that determine the antioxidant capacity of membranes via FSP1-dependent mechanisms using a combination of cellular systems and functional genetic screens.

Conclusion

DeciFERR will lead to a comprehensive understanding of how ferroptosis is orchestrated and will expand the druggable inventory, providing innovative strategies that will be put to test and could ultimately pave the way for efficacious therapies against malignancies that still defy current treatments.